Non-invasive examination of live cell function in real time is essential in advancing understanding of the mechanistic and dynamic progression of biological processes. Understanding the biological processes involved in cell growth and death has a great impact on development of the cell-based drugs. It also complements the existing analytical tools that are aimed at gene and protein identification. The main issue with cellular measurements is that the physical properties do not directly report on a specific molecular target in a given cellular pathway. However, loss of homeostasis, alterations in molecular function and deregulation of molecular pathways inevitably manifest themselves as detectable physical changes in cellular properties.
There are numerous methods being used to monitor biological cell activity, where optical microscopy, hemacytometry, and flow cytometry are standard techniques. However, these standard methods often involve invasively killing the cells and tagging them with optically active biomolecules to obtain information about their growth, proliferation, and function. Recently, there has been an increased interest in developing non-invasive and label-free techniques in monitoring cell function. In vivo flow cytometry is one of the most recent developments in non-invasive cell monitoring, but is not label free. See Irene Georgakoudi, Nicolas Solban, John Novak, William L. Rice, Xunbin Wei, Tayyaba Hasan, and Charles P. Lin, “In Vivo Flow Cytometry: A New Method for Enumerating Circulating Cancer Cells,” Cancer Research 64, 5044-5047, Aug. 1, 2004. It combines confocal microscopy and flow cytometry and is only limited to cells that are circulating in the bloodstream. This method is only used in animals, where cells are still invasively tagged with fluorescent markers to act as the label for the confocal microscope. Furthermore, due to expensive equipment and complicated operation involved, it is impossible to simultaneously monitor large numbers of the samples in real-time.
Non-optical biosensing devices have also been employed in cellular monitoring techniques. These devices are more compact and cost effective than the optical method. The most common method is the impedance spectrum analysis using the standard quartz crystal microbalance (QCM) and the QCM with dissipation (QCM-D), and the E-Plate impedance sensor. These techniques however are not very sensitive to viscoelastic transitions occurring in biological samples. Moreover, since their sensing area surfaces are not controllable, they also require surface-conditioning chemicals to facilitate bio-adhesion to the metallic sensing surface and involves only a limited number of these compatible chemicals. See C. Fredriksson, S. Kihlman, M. Rodahl, B. Kasemo, “The Piezoelectric Quartz Crystal Mass and Dissipation Sensor: A Means of Studying Cell Adhesion,” Langmuir, 14 248-251, 1998; X. C. Zhou, L. Q. Huang, and S. F. Y. Li, “Microgravimetric DNA sensor based on quartz crystal microbalance: comparison of oligonucleotide immobilization methods and the application in genetic diagnosis,” Biosensors & Bioelectronics, vol. 16, pp. 85, 2001, M. Muratsugu, F. Ohta, Y. Miya, T. Hosokawa, S. Kurosawa, N. Kamo, and H. Ikeda, “Quartz crystal microbalance for the detection of microgram quantities of human serum albumin: relationship between the frequency change and the mass of protein adsorbed,” Analytical Chemistry, vol. 65, pp. 2933, 1993.
Accordingly, there is an immediate need for improved sensors and related sensing methods.